Multiple myeloma (MM), a plasma cell neoplasm, comprises approximately 10% of all hematologic malignancies (1). The clinical success of the proteasome inhibitor (PI) bortezomib in MM has validated the ubiquitin-proteasome system (UPS) as a compelling target for drug development (2). The proteasome is a multi-subunit protein complex responsible for degrading misfolded and damaged proteins as well as intracellular signaling intermediates (3). Because of their dysregulated signaling pathways, neoplastic cells rely heavily on the UPS, and therefore are particularly sensitive to proteasome inhibition (4). Apoptosis of MM cells following proteasome inhibition occurs through multiple mechanisms, including down-regulation of prosurvival NF-κB signaling, inhibition of angiogenesis, activation of a misfolded protein stress response, induction of intrinsic and extrinsic cell death pathways, and inhibition of MM cell adhesion to the bone marrow stromal cells (5-8).
The first PI in clinical development, bortezomib (also known as PS-341 or [(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid), was approved by the FDA in 2003 following two successful single-agent phase II trials in relapsed MM (9,10). Bortezomib also shows remarkable activity in combination with other agents. In preclinical studies, subtoxic concentrations of bortezomib overcame the resistance of MM cells to chemotherapeutic drugs, including melphalan, doxorubicin, or mitoxantrone (11-13). In addition, bortezomib potentiates the activity of novel therapies for MM, including lenalidomide, arsenic trioxide, and inhibitors of histone deacetylase or PKC, as well as second-generation PIs (14-18). Synergistic in vitro activity has translated to enhanced in vivo efficacy in clinical studies testing bortezomib-based combination therapies. In the phase III VISTA trial evaluating melphalan and prednisone (MP) with or without bortezomib (V), VMP was associated with a 3-year overall survival rate of 72%, compared with 59% for MP therapy (P=0.003) (19). Notably, the addition of bortezomib to a regimen can, in some cases, resensitize patients to failed therapies. For example, in a phase II study, 60% of MM patients who relapsed following melphalan treatment subsequently responded to bortezomib/melphalan combination therapy (20). Similarly, bortezomib combined with thalidomide and dexamethasone yielded a 63% overall response rate in a relapsed population of MM patients, 73% of whom had previous exposure to thalidomide (21).
Although the approval of bortezomib has transformed treatment of MM, a sizeable proportion of patients fail to respond to bortezomib therapy. The results of a recent study suggest that differing proteasome expression and activity levels may underlie the variable sensitivity of MM tumors to treatments with PIs (22). Furthermore, even patients who initially respond to bortezomib face almost-certain relapse. Growing evidence suggests that a small population of drug-resistant cancer stem cells may be responsible for recurrence of MM following remission (23-26). These cells express surface antigens characteristic of normal memory B cells, lack the plasma cell marker CD138, and do not secrete antibody (24). Furthermore, when challenged with commonly used anti-myeloma drugs (e.g., dexamethasone, lenalidomide, cyclophosphamide) the CD138-negative stem cell population shows greater drug resistance than the rest of the malignant cell population (24). Single-agent bortezomib, for example, is active against MM cells that produce high amounts of immunoglobulin (27), but has little effect on growth of CD138-negative MM cells (24). These data highlight the need for new MM therapies that target cancer stem cells, as well as the remainder of the malignant plasma cell subtypes within the tumor population
A search for novel, more potent, or better-tolerated PIs resulted in the synthesis of COMPOUND 1 (also known as [(1R)-1-[[(2S,3R)-3-hydroxy-2-[6-phenyl-pyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutylboronic acid; Bernardini, et al., U.S. Application No. US 2005/0107307). Like bortezomib, COMPOUND 1 is a reversible PI in the peptide boronic acid class (28). In contrast to bortezomib, which is administered by intravenous (IV) bolus, COMPOUND 1 is active as an oral formulation in preclinical studies (28,29). Furthermore, COMPOUND 1 shows similar or better single-agent antitumor activity when compared with bortezomib, both in primary MM plasma cells in vitro and in RPMI8226 mM xenografts in vivo (29). COMPOUND 1 has the following chemical structure:

There remains a need for treatment options that can offer the best long-term outcome for multiple-myeloma patients. The need is especially urgent for novel therapies for patients with relapsed or refractory disease. Until the study disclosed herein, the combination therapy of COMPOUND 1 with either bortezomib or melphalan had never been investigated. These combination therapies offer attractive treatment options for MM patients, including those with relapsed or refractory disease.
All references cited are hereby incorporated by reference.